Our research application is addressing PQ8: Why do certain mutational events promote cancer phenotypes in some tissues and not in others? The goal of our proposed research is to identify factors responsible for tissue-selective tumorigenesis following inactivation of a tumor suppressor gene. Multiple Endocrine Neoplasia type 1 (MEN1), a familial cancer syndrome characterized by tissue-restricted tumorigenesis, provides a unique and tractable model with which to accomplish this goal. Bi-allelic inactivation of Men1, a ubiquitously expressed tumor suppressor encoding the transcription factor menin, is required for tumorigenesis in MEN1. Our experiments using Cre-lox deletion of Men1 demonstrates that differential inactivation of Men1 in various tissues does not explain the tissue restricted nature of tumors in MEN1. Rather, additional factors are required to enhance or suppress tumorigenesis in tissues that have lost Men1. For example, homozygous deletion of Men1 in all cells of the pancreas results in tumors in the endocrine tissue but not exocrine tissue of the same organ. Given that inactivation of Men1 is tightly linked to MEN1, we postulate that operation of these modulating factors is regulated by loss of menin. Our central hypothesis is that loss of menin differentially regulates expression of factors that influence carcinogenesis in various tissues so as to generate the tissue restricted characteristic of tumor formation in MEN1. To test this hypothesis, we propose to undertake both unbiased, genome wide screens and candidate approaches to identify relevant factors. Aim 1 employs ChIP- Seq and RNA-Seq respectively to identify DNA binding sites for menin that are differentially occupied and transcriptomes that are differentially expressed in tissues that develop MEN1 tumors versus those that do not. Specifically, we will compare tissues from the endocrine pancreas (develops tumors) versus the exocrine pancreas (does not develop tumors). Aim 2 will validate these findings in the parathyroid gland, a second site of tumor development in MEN1. Aim 3 will explore the role of the candidate protein ARC, an apoptosis inhibitor and cell cycle promoter that has already been implicated in mammary carcinogenesis. Our preliminary studies show that ARC is up-regulated by deletion of Men1 in the endocrine pancreas and parathyroid gland, but not in the exocrine pancreas. Moreover, ChIP-CHIP studies suggest that menin binds to the promoter of nol3, the gene encoding ARC. Taken together, these studies will provide novel and important insights into why tumors develop in some tissues and not in others following loss of a tumor suppressor gene. PUBLIC HEALTH RELEVANCE: Tumor suppressors are genes that inhibit cancer development. When tumor suppressors are lost, cancers develop. Surprisingly, however, these cancers develop only in some tissues, but not others. The goal of this grant application is to discover why.